Investigation of fibrotic factors during the exon-skipping therapy using antisense oligonucleotide for muscular dystrophy

为了提高反义寡核苷酸（AO）介导的外显子跳跃治疗Duchenne型肌营养不良症（DMD）的有效性，研究了纤维化和炎症与DMD的关系。在开始时，使用无细胞剪接系统检查了AO诱导外显子45（AO 85）跳读的药效学，并且AO 85的EC 50显示为58.0 nM。尿中前列腺素D_2的主要代谢产物四氢吡喃PGDM在DMD患者中升高，并随年龄增长而升高。提示PGD2介导的炎症反应在DMD的病理过程中起一定作用。此外，对DMD病例施用AO85导致一些炎性细胞因子的改善。这些结果表明纤维化和炎症参与了DMD的发病机制，并且这些因素的修饰被认为是增强AO介导的外显子跳跃治疗的有效性的可能策略之一。

To enhance the effectiveness of antisense oligonucleotide (AO)-mediated exon skipping therapy for Duchenne muscular dystrophy (DMD), the relationship of fibrosis and inflammation to DMD was examined. At the beginning pharmacodynamics of the AO inducing the skipping of exon 45(AO85) was examined using cell-free splicing system, and the EC50 of AO85 was revealed to be 58.0 nM. Then, urinary tetranor PGDM which is major urinary metabolite of prostaglandin (PG) D2 were shown to be increased in DMD patients and became higher with advancing age. It was indicated that PGD2-mediated inflammation plays a role in the pathology of DMD. Furthermore, administration of AO85 to DMD cases resulted in the improvement of some inflammatory cytokines. These results indicated that fibrosis and inflammation were involved in the pathogenesis of DMD, and the modification of these factors was considered as one possible strategy for the enhancement of the effectiveness of AO-mediated exon skipping therapy.